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Recent evidence demonstrates that vessel involvement is crucial in various bone remodeling situations, indicating that blood vessel formation within or surrounding the implant is essential for establishment of rigid implant fixation. In this work, the ability of the silicon-doped porous TiO 2 coatings fabricated via plasma electrolyte oxidation method (PEO) to enhance the angiogenic potential of human umbilical vein endothelial cells (HUVECs) were investigated. The cellular responses of HUVECs on the silicon-doped porous TiO 2 coatings were studied through cell proliferation, vascular endothelial growth factor (VEGF) secretion, and angiogenic-associated gene (VEGF, HIF-1α and HGF) expression analysis. The results show that small amount of silicon significantly enhanced angiogenic activity of HUVECs, while larger amount of silicon appears excessive. Hence, the silicon-doped TiO 2 coating offers a potential solution to improve bone vascularization to achieve efficient osseointegration and restoration of function after implantation. [ABSTRACT FROM AUTHOR]

Biodegradable magnesium-based alloys have shown great potential for medical applications due to their superior biological performances and mechanical properties. However, on one hand, some side effects including inferior biocompatibility, a local high-alkaline environment and gas cavities caused by a rapid corrosion rate, hinder their clinical application. On the other hand, it is also necessary to endow Mg alloys with antibacterial properties, which are crucial for clinic orthopedic applications. In this study, Zr and N ions are simultaneously implanted into AZ91 Mg alloys by plasma immersion ion implantation (PIII). A modified layer with a thickness of approximately 80 nm is formed on the surface of AZ91 Mg alloys, and the hydrophobicity and roughness of these AZ91 Mg alloys obviously increase after Zr and N implantation. The in vitro evaluations including corrosion resistance tests, antimicrobial tests and cytocompatibility and alkaline phosphatase (ALP) activity tests, revealed that the dual ions implantation of Zr and N not only enhanced the corrosion resistance of the AZ91 Mg alloy but also provided better antimicrobial properties in vitro . Furthermore, the formation of biocompatible metal nitrides and metal oxides layer in the near surface of the Zr-N-implanted AZ91 Mg alloy provided a favorable implantation surface for cell adhesion and growth, which in return further promoted the bone formation in vivo . These promising results suggest that the Zr-N-implanted AZ91 Mg alloy shows potential for future application in the orthopedic field. [ABSTRACT FROM AUTHOR]

Abstract: Rapid development of zinc biology has broadened the applications of Zn-incorporated biomaterials to tissue engineering but also raised concerns about the long-term safety of released Zn2+ ions. Clinical success hinges on the amount of incorporated zinc and subsequent optimized release sufficient to stimulate osseointegration. In this study, zinc is incorporated into the sub-surface of TiO2 coatings by plasma immersion ion implantation and deposition (PIII&D). The Zn-implanted coatings show significant improvement compared to the “bulk-doped” coatings prepared by plasma electrolyte oxidation in terms of osteogenesis in vitro and in vivo. Molecular and cellular osteogenic activities demonstrate that rBMSCs cultured on the Zn-implanted coatings have higher ALP activity and up-regulated osteogenic-related genes (OCN, Col-I, ALP, Runx2) compared to the bulk-doped Zn coatings and controls. In vivo osseointegration studies conducted for 12 weeks on the rat model show early-stage new bone formation and the bone contact ratio (12 week) on the Zn-implanted coating is larger. The ZnT1 and ZIP1 gene expression studies demonstrate that the Zn-implanted coatings can better stimulate bone growth with reduced Zn release than those doped with zinc throughout the coatings. [Copyright &y& Elsevier]

Abstract: To improve the bioactivity and cytocompatibility of biomedical titanium dioxide coating, many efforts have been made to modify its surface composition and topography. Meanwhile, CaSiO3 was commonly investigated as coating material on titanium implants for fast fixation and firm implant-bone attachment due to its demonstrated bioactivity and osteointegration. In this work, gradient TiO2/CaSiO3 coating on titanium was prepared by a two-step procedure, in which porous and nanostructured TiO2 coating on titanium was prepared by plasma electrolytic oxidation in advance, and then needle and flake-like CaSiO3 nanocrystals were deposited on the TiO2 coating surface by electron beam evaporation. In view of the potential clinical applications, apatite-forming ability of the TiO2/CaSiO3 coating was evaluated by simulated body fluid (SBF) immersion tests, and MG63 cells were cultured on the surface of the coating to investigate its cytocompatibility. The results show that deposition of CaSiO3 significantly enhanced the apatite-forming ability of nanostructured TiO2 coating in SBF. Meanwhile, the MG63 cells on TiO2/CaSiO3 coating show higher proliferation rate and vitality than that on TiO2 coating. In conclusion, the porous and nanostructured TiO2/CaSiO3 coating on titanium substrate with good apatite-forming ability and cytocompatibility is a potential candidate for bone tissue engineering and implant coating. [Copyright &y& Elsevier]

Abstract: Glutaryl-CoA dehydrogenase catalyzes the oxidative decarboxylation of the γ-carboxylate of the substrate, glutaryl-CoA, to yield crotonyl-CoA and CO2. The enzyme is a member of the acyl-CoA dehydrogenase (ACD) family of flavoproteins. In the present study, the catalytic properties of this enzyme, including its substrate specificity, isomerase activity, and interactions with inhibitors, were systematically studied. Our results indicated that the enzyme has its catalytic properties very similar to those of short-chain and medium-chain acyl-CoA dehydrogenase except its additional decarboxylation reaction. Therefore, the inhibitors of fatty acid oxidation targeting straight chain acyl-CoA dehydrogenase could also function as inhibitors for amino acid metabolism of lysine, hydroxylysine, and tryptophan. [Copyright &y& Elsevier]

Abstract: Silver (Ag) and nitrogen (N) dual ions were sequentially implanted into titanium to prepare the samples including PIII-Ag–N (Ag ions prior to N implantation), PIII-N–Ag (N prior to Ag ions implantation) and PIII-Ag+N (Ag/N dual ions co-implantation) via plasma immersion ion implantation (PIII) technology. All of the samples were characterized by a scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). The antibacterial activity, corrosion resistance and hardness of as-implanted samples were investigated. The results show that the Ag/N dual ions implanted titanium exhibit high bactericidal ability to Escherichia coli and Staphylococcus aureus due to the formation of silver nanoparticles in the near surface region. The zeta potentials show more positive evolution in order of pure titanium, PIII-Ag–N, PIII-N–Ag and PIII-Ag+N, which favors to contact with bacteria thus to inhibit their growth and proliferation. Moreover, the formation of titanium nitride layer during Ag/N dual ions implantation can greatly improve the corrosion resistance and hardness of titanium. The present study suggests that the Ag/N dual ions co-implanted process is the most efficient way to obtain the titanium implant with high antibacterial activity, corrosion resistance and hardness. [Copyright &y& Elsevier]

Abstract: Farnesyltransferase (FTase) and geranylgeranyltransferase type-I (GGTase-I) both catalyze the prenylation of protein substrate containing a typical –CAAX motif at the carboxyl terminus. The inhibitors for these two enzymes have been widely studied as potential cancer chemotherapeutic agents. In the present study, various piperazinedione derivatives were designed and synthesized as a new type of peptide mimetic compounds, which were characterized and found to be dual protein inhibitors for both FTase and GGTase-I. These compounds have similar chemical and physical properties to –CAAX motif of the protein substrate, which may facilitate their transfer to appropriate drug target in vivo. The best inhibitor compound 26b was found to occupy both isoprenoid and peptide substrate binding sites through kinetics and computer molecular docking studies. [Copyright &y& Elsevier]

Reasonable incorporation of manganese into titanium is believed to be able to enhance the osteogenic and antibacterial activities of orthopedic implants. However, it is still a challenge to compromise Mn-induced cytotoxicity and better develop its biocompatibility and antimicrobial ability. To pinpoint this issue, a stable Mn ion release platform was created on Ti using plasma immersion ion implantation and deposition (PIII&D) technique. Compared with as-etched titanium, as a result, promoted antibacterial abilities against gram-negative bacteria species and enhanced osteogenic-related gene expressions on rBMMSC were observed on Mn-containing sample. Meanwhile, the Mn-containing samples showed no obvious cytotoxicity. Our results here provide insight to be better understanding the relationships between additives-induced biological performance and the dose, state, and stability of the doped element. [ABSTRACT FROM AUTHOR]

Alternative antimicrobials are urgently needed due to the antibiotic resistance. Herein, vertical graphene has been in-situ prepared on medical titanium (VG@Ti) by plasma-enhanced chemical vapor deposition for rapid sterilization under near-infrared light. The physicochemical properties, photothermal effect, antibacterial activity, and biocompatibility of VG@Ti were systematically investigated. The results indicated that the thickness of vertical graphene film increased with the augmentation of reaction temperature. Graphene films showed a vertical distribution on medical titanium, which improved the corrosion resistance, hydrophobicity as well as antibacterial ability against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) under near-infrared light. Inhibition rates of 93.3% and 99.1% were achieved for E. coli and S. aureus , respectively, when VG@Ti was exposed to near-infrared light (808 nm) with 0.8 W/cm2 for 10 min. Moreover, vertical graphene on titanium surface exhibit no obvious cytotoxicity to osteoblasts cells. The in vivo results confirmed that vertical graphene with near-infrared light could kill bacteria efficiently and showed no obvious toxicity. Vertical graphene is incorporated on titanium by plasma-enhanced chemical vapor deposition. Vertical graphene has excellent photothermal properties, which can achieve rapid sterilization under near-infrared light. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights: [•] Zn was implanted into titanium using plasma immersion ion implantation technology. [•] The Zn-implanted titanium surfaces exhibited excellent osteogenic activity. [•] The Zn-implanted titanium surfaces possessed partly antibacterial effect. [Copyright &y& Elsevier]

Highlights: [•] Ag-embedded TiO2 film with micropit/nanorod topography was prepared on titanium. [•] The Ag-embedded TiO2 surface exhibited enhanced antimicrobial activity. [•] The Ag-embedded TiO2 surface showed nearly no toxic side effect on the cells. [Copyright &y& Elsevier]

Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor with a high lethal rate. Patients who undergo conventional enucleation treatments consistently suffer permanent blindness, facial defects, and mental disorders, therefore, novel therapeutic modalities are urgently required. Herein, an injectable and stimuli‐responsive drug delivery antibacterial hydrogel (CP@Au@DC_AC50) is constructed via a facile grinding method that is inspired by the preparation process of traditional Chinese medicine. The incorporation of gold nanorods can enhance the mechanical strength of the hydrogel and realize photothermal therapy (PTT) and thermosensitive gel‐sol transformation to release the gene‐targeted drug DC_AC50 on demand in response to low‐density near‐infrared (NIR) light. The orthotopic model of UM is built successfully and indicates the excellent efficiency of CP@Au@DC_AC50 in killing tumors without damage to normal tissue because of its synergistic mild temperature PTT and gene‐targeted therapy. Moreover, the eyeball infection model reveals the remarkable antibacterial properties of the hydrogel which can prevent endophthalmitis in the eyeball. There is negligible difference between the CP@Au@DC_AC50+NIR group and normal group. This NIR light‐triggered gene‐targeted therapy/PTT/antibacterial treatment pattern provides a promising strategy for building multifunctional therapeutic platform against intraocular tumors and exhibits great potential for the clinical treatment of UM. [ABSTRACT FROM AUTHOR]

Near-infrared (NIR) light-triggered photocatalysis antibacterial therapy has attracted significant attention. Herein, we designed a straddle-type heterostructure film of ZnS/Ag 2 S nanorod on the titanium implant, which showed excellent NIR photocatalytic ability. Under NIR, the electrons of Ag 2 S cascaded jump to ZnS conduction band (CB), and the electron of ZnS was half-jumped to Ag 2 S valence band (VB). The VB of Ag 2 S acted as a consumption platform for the holes of Ag 2 S and the electrons of ZnS, improving photocatalytic efficiency. To prove the feasibility of this mechanism, another straddle-type heterostructure of ZnS/Bi 2 S 3 with similar energy band structure was fabricated, and its NIR photocatalytic ability was also distinctly enhanced. Furthermore, the ZnS/Ag 2 S heterostructure films rapidly removed bacteria in vitro and in vivo under the NIR irradiation. This work innovatively discovered NIR photocatalytic effect of the straddle-type heterostructure, which complemented the design of heterostructures in photocatalysis. [Display omitted] • A straddle-type heterostructure of ZnS/Ag2S film was fabricated on titanium. • ZnS/Ag2S straddle-type heterostructure exhibited the enhanced NIR photocatalysis. • This heterostructure film showed good antibacterial efficacy under NIR irradiation. • The enhanced photocatalytic mechanism of the system was clarified and justified. • The NIR photocatalytic mechanism has widespread applicability. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The 3D porous sulfonated polyetheretherhetone (PEEK) was proposed for the application in drug delivery. • Controllable and durable BMP-2 release could be successfully achieved. • The osteogenic differentiation activity of BMP-2-loaded PEEK materials was optimized. Abstract Polyetheretherketone (PEEK) is ideal for dental and orthopedic applications because its mechanical properties are similar to cortical bones. However, its inherent inert ability hinders its clinical applications. In this work, bone morphogenetic protein-2 (BMP-2) was immobilized onto the sulfonated PEEK (SPEEK) using lyophilization technology. The surface morphologies of the samples were analyzed by field-emission scanning electron microscopy (FE-SEM), and the chemical compositions were analyzed by energy-dispersive X-ray spectrometry (EDS). The release content of BMP-2 of the samples immersed in the PBS (pH = 7.4) was detected by a human BMP-2 ELISA kit. The results indicated that controllable and durable BMP-2 release was accomplished due to the three-dimensional (3D) network of sulfonated PEEK. The in vitro cellular experiments showed that the BMP-2-immobilized samples significantly enhanced the initial adhesion and spreading of rat bone mesenchymal stem cells (rBMSCs). Moreover, the collagen secretion, extracellular matrix mineralization and ALP activity were also improved. Thus, the BMP-2-immobilized samples greatly promoted the osteogenic differentiation of rBMSCs, which revealed that BMP-2 immobilization paves the way for the use of PEEK in clinical applications. [ABSTRACT FROM AUTHOR]

Abstract: Construction of localized drug‐eluting systems with synergistic chemothermal tumor‐killing abilities is promising for biomedical implants directly contacting with tumor tissues. In this study, an intelligent and biocompatible drug‐loading platform, based on a gold nanorods‐modified butyrate‐inserted NiTi‐layered double hydroxides film (Au@LDH/B), is prepared on the surface of nitinol alloy. The prepared films function as drug‐loading “sponges,” which pump butyrate out under near‐infrared (NIR) irradiation and resorb drugs in water when the NIR laser is shut off. The stimuli‐responsive release of butyrate is verified to be related with the NIR‐triggered crystal phase transformation of Au@LDH/B. In vitro and in vivo studies reveal that the prepared films possess excellent biosafety and high efficiency in synergistic thermochemo tumor therapy, showing a promising application in the construction of localized stimuli‐responsive drug‐delivery systems. [ABSTRACT FROM AUTHOR]

It is important to fabricate an implant possessing environment sensitive drug delivery. In this work, the construction of 3D porous structure on polyetheretherketone (PEEK) surface and pH sensitive polymer, chitosan, was introduced. The smart release of doxorubicin can be realized on the 3D porous surface of PEEK loading chitosan. We give a feasible explanation for the effect of chitosan on smart drug release according to Henderson–Hasselbalch equation. Furthermore, the intracellular drug content of the cell cultured on the samples with highest chitosan is significantly higher at pH 4.0, whereas lower at pH 7.4 than other samples. The smart release of doxorubicin via modification with chitosan onto 3D porous PEEK surface paves the way for the application of PEEK in drug loading platform for recovering bone defect caused by malignant bone tumor. [ABSTRACT FROM AUTHOR]

The recurrence of bone tumors in the early stage and poor osseointegration in the late stage are the main challenges in the clinical treatment of osteosarcoma. Thus, developing a bone implant with time-ordered anti-tumor and osteogenic abilities may be a promising strategy for osteosarcoma therapy. Here, we constructed a NIR and H 2 O 2 dual-responsive Zr-MOF film composed of Zr ions and ferrocene on the titanium and then loaded the anti-tumor drug doxorubicin (DOX) by electrostatic interaction. Under the stimulation of H 2 O 2 in the tumor microenvironment, the Fe2+ in this Zr-MOF film transformed to Fe3+, which could reduce the negative charge of the Zr-MOF to release DOX. Besides, this drug-loading Zr-MOF film possessed good photothermal conversion capability, which enabled the rapid synthetic anti-tumor effect of chemotherapy and photothermal therapy in the initial stage by using NIR irradiation. In vitro results confirmed that the drug-loading Zr-MOF film exhibited good anti-tumor performance against two kinds of human osteosarcoma cells (Saos-2 and 143B cells), which could be further enhanced by using NIR irradiation, and it also showed good anti-tumor properties in vivo. On the other hand, this Zr-MOF film became super hydrophilic after tumor treatment and then promoted the adhesion and the expression of osteogenic genes (ALP, Col-I, TGF-β, and Runx2) of bone cells. This study provides new sight into the design of bone implants with time-ordered tumor therapy and bone regeneration abilities in practical clinical applications. • A H 2 O 2 and NIR dual-responsive DOX-loaded Zr-MOF film was constructed on titanium. • This Zr-MOF film possess time-ordered anti-tumor and osteogenic properties. • A good anti-tumor effect was achieved under the synthetic photothermal/chemo-therapy. • This Zr-MOF film became hydrophilic after treating tumor to enhance bone formation. [ABSTRACT FROM AUTHOR]

The selective tumor- and bacteria-killing property is promising for biomedical implants in directly contact with tumor tissue but still presents a considerable challenge. In this study, a butyrate-inserted Ni–Ti layered double hydroxide film (LDH/Butyrate) is prepared on the surface of nitinol alloy via a simple hydrothermal treatment. The prepared film can selectively inhibit tumor growth and metastasis and bacterial infection by taking advantage of the overproduced H 2 O 2 in tumor and infection microenvironments: the pro-tumor and pro-infection molecule H 2 O 2 can be consumed by LDH/Butyrate, and cytotoxic butyrate inserted in LDH/Butyrate is subsequently exchanged out. Such a novel endogenous stimuli-responsive platform is expected to prevent tumor overgrowth, metastasis and bacterial infection and will find a promising application in the design of localized drug-eluting systems. [ABSTRACT FROM AUTHOR]

Titanium (Ti) has been widely used as orthopedic and dental implants, it is very important to improve the osteogenic activity and antibacterial ability of titanium implants. The objective of this work was to investigate the osteogenic and antibacterial ability of the zinc (Zn) ion implanted Ti at different implantation voltage. X-ray photoelectron spectroscopy results indicate that Zn was successfully implanted into titanium. Zn-implanted titanium surfaces exhibit enhanced cell proliferation ability, alkaline phosphatase (ALP) activity, and partial resistance to both Escherichia coli ( E . coli ) and Staphylococcus aureus ( S . aureus ). The excellent osteogenic and antibacterial ability are highly related to the implantation voltage. The cell proliferation and antibacterial ability can be enhanced by increasing the implantation voltage from 15 kV to 30 kV, indicating that Zn implantation at 30 kV is more beneficial to both osteogenic and antibacterial ability. [ABSTRACT FROM AUTHOR]

• Defective Ce-BTC nanorods were fabricated on medical titanium surfaces by H-PIII. • ATP deprivation capacity and oxidase-like activity of Ce-BTC were improved by H-PIII. • Ce-BTC treated by H-PIII can effectively prevent biofilm formation and kill bacteria. • Ce-BTC treated by H-PIII for 15 min could promote soft tissue sealing. Implant-associated infections caused by the formation of bacterial biofilms on the implant surface are difficult to cure, which will lead to poor integration between soft tissues and percutaneous implants. To solve this issue, in this work, cerium-based metal-organic framework (Ce-BTC) coatings with abundant coordinative unsaturated metal sites were fabricated on medical titanium surfaces by solvothermal treatment and followed by hydrogen plasma immersion ion implantation (H-PIII) treatment. The surface microstructure of Ce-BTC had no obvious changes after H-PIII treatment, while the crystallinity reduced and the organic ligands were partially etched, resulting in more metal active sites being exposed. Consequently, adenosine triphosphate (ATP) deprivation capacity and oxidase-like activity of Ce-BTC were significantly improved by H-PIII treatment, which could effectively prevent biofilm formation and kill bacteria in response to the bacteria-mediated acidic microenvironment. Moreover, the Ce-BTC treated by H-PIII for 15 min could promote the fibroblast responses including cell proliferation and collagen deposition by up-regulating fibroblast-related genes in vitro , which may be ascribed to the surface nanorod structures and the released Ce ions. The percutaneous infection model in vivo further confirmed that the Ce-BTC treated by H-PIII for 15 min had good antibacterial activity and soft tissue sealing ability, which was conducive to the integration between percutaneous implants and surrounding soft tissues. [ABSTRACT FROM AUTHOR]

Polyetheretherketone (PEEK) is desirable in orthopedic and dental applications because its mechanical properties are similar to those of natural bones but the bioinertness and inferior osteoconduction of PEEK have hampered many clinical applications. In this work, PEEK is sulfonated by concentrated sulfuric acid to fabricate a three-dimensional (3D) network. A hydrothermal treatment is subsequently conducted to remove the residues and the temperature is adjusted to obtain different sulfur concentrations. In vitro cell proliferation and real-time PCR analyses disclose enhanced proliferation and osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs) on the samples with small sulfur concentrations. The in vitro antibacterial evaluation reveals that all the sulfonated samples possess excellent resistance against Staphylococcus aureus and Escherichia coli . The in vivo rat femur implantation model is adopted and X-ray, micro-CT, and histological analyses indicate that not only the premeditated injected bacteria cells are sterilized, but also new bone forms around the samples with small sulfur concentrations. The in vitro and in vivo results reveal that the samples subjected to the hydrothermal treatment to remove excess sulfur have better osseointegration and antibacterial ability and PEEK modified by sulfonation and hydrothermal treatment is promising in orthopedic and dental applications. [ABSTRACT FROM AUTHOR]

Titanium implants possessing simultaneous osseointegration and antibacterial ability are desirable. In this work, three types of Zn/Ag micro-galvanic couples are fabricated on titanium by plasma immersion ion implantation to investigate the osseointegration and antibacterial effects as well as the involved mechanisms. The in vitro findings disclose enhanced proliferation, osteogenic differentiation, and gene expressions of the rat bone mesenchymal stem cells (rBMSCs), as well as good antibacterial ability on all three micro-galvanic couples. Excellent antimicrobial ability is also observed in vivo and the micro-CT and histological results reveal notable osseointegration in vivo despite the presence of bacteria. The Zn/Ag micro-galvanic couple formed on Zn/Ag dual-ion co-implanted titanium shows the best osseointegration as well as good antibacterial properties in vivo obtained from a rabbit tibia model. The difference among the three Zn/Ag micro-galvanic couples can be ascribed to the contact between the Ag NPs and Zn film, which affects the corrosion process. Our results indicate that the biological behavior can be controlled by the corrosion process of the Zn/Ag micro-galvanic couples. [ABSTRACT FROM AUTHOR]

Bacterial infections in wounds often delay the healing process which threaten human health and life. The development of biocompatible hydrogels with antibacterial activity and self-healing to achieve excellent wound closure effectiveness is highly desirable in clinical applications. Herein, a new class of highly stretchable, biocompatible, and antibacterial hydrogel dressings called BPP hydrogel is designed and prepared by chemically cross-linking β-CD with PEI and then physically cross-linking with PVA. The BPP hydrogel exhibits superior properties including excellent antibacterial properties against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli , good biocompatibility for mouse fibroblasts, mouse embryonic fibroblasts and human umbilical vein endothelial cells, outstanding deformability and self-healing performance to protect the wound completely even in special scenes such as pulling and bending. Besides, after damage, the broken BPP hydrogel could heal together, and the healed BPP hydrogel could be stretched to 150% breaking deformation. Furthermore, in vivo experiments further verify that BPP hydrogel has excellent sterilization and healing effect on infectious wounds. This work proves that BPP hydrogel would be a promising material for wound healing and has good prospect for clinical translation. [Display omitted] • A composite hydrogel containing β-CD, PEI, and PVA was fabricated via chemical and physical cross-linking. • The incorporation of PEI endows this composite hydrogel with superior antibacterial activity. • This composite hydrogel exhibited good self-healing property due to the presence of intermolecular forces. • Mechanisms of this hydrogel for wound healing in the presence of S. aureus were revealed. [ABSTRACT FROM AUTHOR]

[Display omitted] • A hierarchical coating composed of Ca-O-Ti and MgO layer was tailored on titanium. • The hierarchical coating produced a time-varying local alkaline microenvironment. • The alkaline microenvironment had antibacterial and osteogenic abilities. • The hierarchical coating inhibited infection and promoted bone formation in vivo. Initial implant-associated infection and later poor osseointegration are the main obstacles for bone implant success. Therefore, it is essential to endow implants with sequential antibacterial and osteogenic properties. However, bacteria and host cells share similar response mechanisms to external environments, so up to now, designing such implants remains a challenge. Here, we proposed a novel strategy of tailoring a time-varying surface alkaline microenvironment for sequential anti-infection and osteointegration, which was realized by constructing a two-layer hierarchical coating on the titanium with Ca-O-Ti as the inner layer and MgO as the outer layer. At the early stage of bone implantation, the outer MgO film rapidly generates a local strong alkaline microenvironment that disrupts bacterial energy metabolism and kills bacteria; at the later stage, the inner Ca-O-Ti layer maintains a long-term local weak alkaline microenvironment, which promotes stem cell adhesion, proliferation, and osteogenic differentiation to achieve successful osteointegration. The results of an in vivo experiment using a rat osteomyelitis model confirmed that the hierarchical coating inhibited infection and promoted the formation of new bone. This study demonstrates the potential of tailoring a time-varying alkaline microenvironment for sequential anti-infection and osteointegration, as a promising and safe strategy for the surface modification of bone implants. [ABSTRACT FROM AUTHOR]

Abstract: As an implantable material, carbon-fiber-reinforced polyetheretherketone (CFRPEEK) possesses an adjustable elastic modulus similar to that of cortical bone and is a prime candidate to replace metallic surgical implants. However, the bioinertness and poor osteogenic properties of CFRPEEK limit its clinical application as orthopedic implants. In this work, titanium ions are introduced energetically into CFRPEEK by plasma immersion ion implantation (PIII). Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) reveal the formation of nanopores with the side wall and bottom embedded with ∼20 nm TiO2 nanoparticles on the CFRPEEK surface. Nanoindentation measurements confirm the stability and improved elastic resistance of the structured surfaces. In vitro cell adhesion, viability assay, and real-time PCR analyses disclose enhanced adhesion, proliferation, and osteo-differentiation of rat bone mesenchymal stem cells (bMSCs). The multilevel structures on CFRPEEK also exhibit partial antibacterial activity to Staphylococcus aureus and Escherichia coli. Our results indicate that a surface with multifunctional biological properties can be produced by multilevel surface engineering and application of CFRPEEK to orthopedic and dental implants can be broadened and expedited based on this scheme. [Copyright &y& Elsevier]

The micro-galvanic couples formed by silver and the titanium matrix can stimulate the opening of voltage-gated calcium channels in macrophages and facilitate Ca2+ influx. Intracellular Ca2+ and calcium-dependent PGE2 secreted by cells can promote the polarization of macrophages, especially the M2 phenotype, and regulate the immune response. Meanwhile, these micro-galvanic couples can kill adherent bacteria and influence the osteogenesis of stem cells. [Display omitted] • Micro-galvanic couples have been formed on Ag-doped titanium substrate. • Micro-galvanic couples activate voltage-gated calcium channels on macrophages. • Ca2+ is prone to M2 macrophages activation through PGE2 secretion. • Bone marrow mesenchymal stem cells promote the polarization of M2 macrophages. To explore the physiological mechanism of silver for the clinical application of silver-containing biomaterials and biomedical devices, the plasma immersion ion implantation method was used to prepare silver-doped titanium samples in this work. The findings disclosed that with the increase of the introduced Ag amount, the micro-galvanic effects formed by silver and the titanium matrix became stronger, which could stimulate the opening of voltage-gated calcium channels in macrophages to facilitate Ca2+ influx. The increase of intracellular Ca2+ concentration could induce macrophages to polarize towards the M1 phenotype by activating the Ca2+-dependent PKC-NF-κB signaling pathway, while it was more favorable to the polarization of M2 macrophages by improving the synthesis and secretion of calcium-dependent PGE2. Therefore, with the increase of Ag amount, the micro-galvanic effect was enhanced, and the anti-inflammatory responses of macrophages on samples were improved. Furthermore, the co-cultured bone marrow mesenchymal stem cells could inhibit the Ca2+ influx of the co-cultured macrophages to down-regulate the Ca2+-dependent PKC-NF-κB signaling pathway in macrophages and secrete PGE2 to promote the polarization of M2 macrophages, which weaken the inflammatory response. Our results indicate that the immune response can be regulated by the micro-galvanic effects of silver and titanium matrix, and provide new insights into designing and developing the silver-containing biomaterials with a desirable biological response. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mevalonate pathway is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria. Four enzymes in mevalonate pathway, including MVK, PMK, MDD, and FPPS, play important regulatory roles in cholesterol biosynthesis and cell proliferation. Methods: The following methods were used: cloning, expression and purification of enzymes in mevalonate pathway, organic syntheses of multifunctional enzyme inhibitors, measurement of their IC50 values for above four enzymes, kinetic studies of enzyme inhibitions, molecular modeling studies, cell viability tests, and fluorescence microscopy. Results and conclusions: We report our multi-target-directed design, syntheses, and characterization of two blue fluorescent bisphosphonate derivatives compounds 15 and 16 as multifunctional enzyme inhibitors in mevalonate pathway. These two compounds had good inhibition to all these four enzymes with their IC50 values at nanomolar to micromolar range. Kinetic and molecular modeling studies showed that these two compounds could bind to the active sites of all these four enzymes. The fluorescence microscopy indicated that these two compounds could easily get into cancer cells. General significance: Multifunctional enzyme inhibitors are generally more effective than single enzyme inhibitors, with fewer side effects. Our results showed that these multifunctional inhibitors could become lead compounds for further development for the treatment of soft-tissue tumors and hypercholesteremia. [Copyright &y& Elsevier]

Abstract: Mevalonate 5-diphosphate decarboxylase plays an important role in regulating cholesterol biosynthesis, which was studied through incubation with various synthetic substrate analogs and characterization of mutated enzymes. The results are potentially useful for further developing inhibitors that block the mevalonate pathway which is a drug target for treating cardiovascular disease and cancer. [Copyright &y& Elsevier]

The mevalonate pathway is an important drug target for the treatment of cancer and cardiovascular disease. We synthesized and studied a new type of nitrogen-containing bisphosphonate analogs and developed a sensitive end point assay method for enzyme FPPS, which was used for inhibitor screening. One potent FPPS inhibitor was discovered, and the structure–activity relationship of bisphosphonates for the enzyme inactivation was studied. [ABSTRACT FROM AUTHOR]